The influence of particle size and multiple apoprotein E-receptor interactions on the endocytic targeting of β-VLDL in mouse peritoneal macrophages

Ira Tabas, Jeffrey N. Myers, Thomas L. Innerarity, Xiangxi Xu, Kay Arnold, Janet Boyles, Frederick R. Maxfield

Research output: Contribution to journalArticle

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Abstract

Low density lipoprotein (LDL) and β-very low density lipoprotein (β-VLDL) are internalized by the same receptor in mouse peritoneal macrophages and yet their endocytic patterns differ; β-VLDL is targeted to both widely distributed and perinuclear vesicles, whereas LDL is targeted almost entirely to perinuclear lysosomes. This endocytic divergence may have important metabolic consequences since β-VLDL is catabolized slower than LDL and is a more potent stimulator of acyl-CoA/cholesterol acyl transferase (ACAT) than LDL. The goal of this study was to explore the determinants of β-VLDL responsible for its pattern of endocytic targeting. Fluorescence microscopy experiments revealed that large, intestinally derived, apoprotein (Apo) E-rich β-VLDL was targeted mostly to widely distributed vesicles, whereas small, hepatically derived β-VLDL was targeted more centrally (like LDL). Furthermore, the large β-VLDL had a higher ACAT-stimulatory potential than the smaller β-VLDL. The basis for these differences was not due to fundamental differences in the means of uptake; both large and small β-VLDL were internalized by receptor-mediated endocytosis (i.e., not phagocytosis) involving the interaction of Apo E of the β-VLDL with the macrophage LDL receptor. However, large β-VLDL was much more resistant to acid-mediated release from LDL receptors than small β-VLDL. Furthermore, partial neutralization of the multiple Apo Es on these particles by immunotitration resulted in a more perinuclear endocytic pattern, a lower ACAT-stimulatory potential, and an increased sensitivity to acid-mediated receptor release. These data are consistent with the hypothesis that the interaction of the multivalent Apo Es of large β-VLDL with multiple macrophage LDL receptors leads to a diminished or retarded release of the β-VLDL from its receptor in the acidic sorting endosome which, in turn, may lead to the widely distributed endocytic pattern of large β-VLDL. These findings may represent a physiologically relevant example of a previously described laboratory phenomenon whereby receptor cross-linking by multivalent ligands leads to a change in receptor targeting.

Original languageEnglish
Pages (from-to)1547-1560
Number of pages14
JournalJournal of Cell Biology
Volume115
Issue number6
StatePublished - Dec 1 1991
Externally publishedYes

Fingerprint

Peritoneal Macrophages
Apolipoproteins E
LDL Lipoproteins
Particle Size
Acyl Coenzyme A
LDL Receptors
Transferases
Apoproteins
Cholesterol
Macrophages
Acids
VLDL Lipoproteins
Endosomes
Endocytosis
Lysosomes
Fluorescence Microscopy
Phagocytosis
Ligands

ASJC Scopus subject areas

  • Cell Biology

Cite this

The influence of particle size and multiple apoprotein E-receptor interactions on the endocytic targeting of β-VLDL in mouse peritoneal macrophages. / Tabas, Ira; Myers, Jeffrey N.; Innerarity, Thomas L.; Xu, Xiangxi; Arnold, Kay; Boyles, Janet; Maxfield, Frederick R.

In: Journal of Cell Biology, Vol. 115, No. 6, 01.12.1991, p. 1547-1560.

Research output: Contribution to journalArticle

Tabas, Ira ; Myers, Jeffrey N. ; Innerarity, Thomas L. ; Xu, Xiangxi ; Arnold, Kay ; Boyles, Janet ; Maxfield, Frederick R. / The influence of particle size and multiple apoprotein E-receptor interactions on the endocytic targeting of β-VLDL in mouse peritoneal macrophages. In: Journal of Cell Biology. 1991 ; Vol. 115, No. 6. pp. 1547-1560.
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AB - Low density lipoprotein (LDL) and β-very low density lipoprotein (β-VLDL) are internalized by the same receptor in mouse peritoneal macrophages and yet their endocytic patterns differ; β-VLDL is targeted to both widely distributed and perinuclear vesicles, whereas LDL is targeted almost entirely to perinuclear lysosomes. This endocytic divergence may have important metabolic consequences since β-VLDL is catabolized slower than LDL and is a more potent stimulator of acyl-CoA/cholesterol acyl transferase (ACAT) than LDL. The goal of this study was to explore the determinants of β-VLDL responsible for its pattern of endocytic targeting. Fluorescence microscopy experiments revealed that large, intestinally derived, apoprotein (Apo) E-rich β-VLDL was targeted mostly to widely distributed vesicles, whereas small, hepatically derived β-VLDL was targeted more centrally (like LDL). Furthermore, the large β-VLDL had a higher ACAT-stimulatory potential than the smaller β-VLDL. The basis for these differences was not due to fundamental differences in the means of uptake; both large and small β-VLDL were internalized by receptor-mediated endocytosis (i.e., not phagocytosis) involving the interaction of Apo E of the β-VLDL with the macrophage LDL receptor. However, large β-VLDL was much more resistant to acid-mediated release from LDL receptors than small β-VLDL. Furthermore, partial neutralization of the multiple Apo Es on these particles by immunotitration resulted in a more perinuclear endocytic pattern, a lower ACAT-stimulatory potential, and an increased sensitivity to acid-mediated receptor release. These data are consistent with the hypothesis that the interaction of the multivalent Apo Es of large β-VLDL with multiple macrophage LDL receptors leads to a diminished or retarded release of the β-VLDL from its receptor in the acidic sorting endosome which, in turn, may lead to the widely distributed endocytic pattern of large β-VLDL. These findings may represent a physiologically relevant example of a previously described laboratory phenomenon whereby receptor cross-linking by multivalent ligands leads to a change in receptor targeting.

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